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The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress

Nature Medicine volume 13, pages 619–624 (2007)Cite this article

Abstract

Autophagy, an evolutionarily conserved process for the bulk degradation of cytoplasmic components, serves as a cell survival mechanism in starving cells1,2. Although altered autophagy has been observed in various heart diseases, including cardiac hypertrophy3,4 and heart failure5,6, it remains unclear whether autophagy plays a beneficial or detrimental role in the heart. Here, we report that the cardiac-specific loss of autophagy causes cardiomyopathy in mice. In adult mice, temporally controlled cardiac-specific deficiency of Atg5 (autophagy-related 5), a protein required for autophagy, led to cardiac hypertrophy, left ventricular dilatation and contractile dysfunction, accompanied by increased levels of ubiquitination. Furthermore, Atg5-deficient hearts showed disorganized sarcomere structure and mitochondrial misalignment and aggregation. On the other hand, cardiac-specific deficiency of Atg5 early in cardiogenesis showed no such cardiac phenotypes under baseline conditions, but developed cardiac dysfunction and left ventricular dilatation one week after treatment with pressure overload. These results indicate that constitutive autophagy in the heart under baseline conditions is a homeostatic mechanism for maintaining cardiomyocyte size and global cardiac structure and function, and that upregulation of autophagy in failing hearts is an adaptive response for protecting cells from hemodynamic stress.

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Figure 1: Cardiac dysfunction in tamoxifen-treated Atg5flox/flox;MerCreMer+ mice.
Figure 2: Hypertrophic responses in tamoxifen-treated Atg5flox/flox;MerCreMer+ mice.
Figure 3: Biochemical and histological abnormalities in tamoxifen-treated Atg5flox/flox;MerCreMer+ mice.
Figure 4: Pressure overload induces cardiac dysfunction in Atg5flox/flox;MLC2v-Cre+ mice.

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Acknowledgements

We are grateful to K. Chien (Harvard University) for the gift of MLC-2v Cre mice, J. Molkentin (Cincinnati Children's Hospital Medical Center) for MerCreMer mice, T. Yoshimori (Osaka University) for antibody to LC3 and E. Lakatta for teaching us to isolate adult mouse cardiomyocytes. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology to K.O. (16590683). O.Y. held a postdoctoral fellowship from the Japan Society for the Promotion of Science. S.H. was the recipient of a postdoctoral fellowship from the Center of Excellence Research of the Ministry of Education, Culture, Sports, Science and Technology. T.T. received a postdoctoral fellowship from the Japan Health Science Foundation.

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Author notes

  1. Atsuko Nakai and Osamu Yamaguchi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Atsuko Nakai, Osamu Yamaguchi, Toshihiro Takeda, Yoshiharu Higuchi, Shungo Hikoso, Masayuki Taniike, Shigemiki Omiya, Isamu Mizote, Kazuhiko Nishida, Masatsugu Hori & Kinya Otsu

  2. Department of Medical Information Science, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Yasushi Matsumura

  3. Department of Biochemistry, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Michio Asahi

  4. Department of Bioregulation and Metabolism, Tokyo Metropolitan Institute of Medical Science, Bunkyoku, Tokyo, 113-8613, Japan

    Noboru Mizushima

  5. Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Bunkyoku, Tokyo, 113-8519, Japan

    Noboru Mizushima

  6. Solution-Oriented Research for Science and Technology, Japan Science and Technology Agency, 4-1-8 Honmachi, Kawaguchi, 332-0012, Saitama, Japan

    Noboru Mizushima

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  1. Atsuko Nakai
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Contributions

A.N. worked on the in vitro analysis of the mice; O.Y. conducted the in vivo analysis of the mice and wrote the manuscript; T.T. performed adult cardiomyocyte isolation and Ca2+ transient experiments; Y.H. performed ischemia-reperfusion surgery; S.H. assisted with RT-PCR experiments; M.T., S.O. and I.M. contributed to the in vitro experiments; Y.M. performed statistical analysis of the data; M.A. contributed to Ca2+ transient measurements; K.N. contributed to the in vivo experiments; M.H. supervised this project; N.M. provided advice on designing and conducting experiments; K.O. conceived, designed and directed the study.

Corresponding author

Correspondence to Kinya Otsu.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Inhibition of autophagy using adenovirus expressing shRNA against Atg7. (PDF 617 kb)

Supplementary Fig. 2

Characterization of Atg5flox/flox; MLC2v-Cre+ mice. (PDF 235 kb)

Supplementary Fig. 3

Pressure overload induces cardiac dysfunction in Atg5flox/flox; α-MyHC-Cre+ mice. (PDF 372 kb)

Supplementary Fig. 4

Autophagy in pressure overload-induced cardiac remodeling. (PDF 236 kb)

Supplementary Fig. 5

Biochemical analysis of Atg5flox/flox; MLC2v-Cre+ hearts after TAC. (PDF 287 kb)

Supplementary Fig. 6

β-adrenergic stress induces cardiac dysfunction in Atg5flox/flox; MLC2v-Cre+ mice. (PDF 627 kb)

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Nakai, A., Yamaguchi, O., Takeda, T. et al. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med 13, 619–624 (2007). https://doi.org/10.1038/nm1574

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